The prostaglandins are a biologically important class of naturally occurring acids that are derived, in a formal sense, by functionalization of the fundamental alicyclic C.sub.20 fatty acid, prostanoic acid. ##STR2##
The naturally occurring prostaglandins are known to have a broad spectrum of biological activity. In particular, the E-series prostaglandins number among their useful actions hypotensive, renal vasodilatory, gastric antisecretory, bronchodilatory, and platelet aggregation inhibitory activities.
There is much evidence to show that the E prostaglandins express these activities by elevating the levels of cyclic adenosine monophosphate (CAMP) in the target cells. The compounds of this invention mimic the E prostaglandins in biological activity since they likewise markedly stimulate the formation of CAMP. For example, a compound of formula I, 7-[3-(3-hydroxy-1-trans-octenyl)-2-isothiazolidinyl]-5-cis-heptenoic acid S,S-dioxide, causes a 14-fold increase in CAMP compared to control in the mouse ovary at a concentration of 25 micrograms per milliliter.
The compounds of this invention are thus applicable to therapy particularly as (1) renal vasodilators for the treatment of patients with renal impairment, (2) hypotensives for the normalization of high blood pressure, and (3) platelet aggregation inhibitors useful in preventing the formation of thrombi.
Further, a major disadvantage of the prostaglandins has been overcome by the compounds of this invention. The prostaglandins are so rapidly metabolized and deactivated in bodily tissues that their actions are hardly seen except on intravenous administration. Adequate blood levels cannot be attained when the prostaglandins are administered orally. The compounds of this invention are not substrates for the principal prostaglandin degrading enzyme. They are thus only slowly metabolized, have adequate durations of action, and are biologically active when administered orally.
The compounds of this invention can be administered either topically or systemically, i.e., intravenously, subcutaneously, intramuscularly, orally, rectally, or by aerosolization in the form of sterile implants for long action. They can be formulated in any of a number of pharmaceutical compositions and non-toxic carriers to this end.
The pharmaceutical compositions can be sterile, injectable suspensions or solutions, or solid orally-administrable, pharmaceutically acceptable tablets or capsules; the compositions can also be intended for sublingual administration, or for suppository use. It is especially advantageous to formulate compositions in dosage unit forms for ease and economy of administration and uniformity of dosage. "Dosage unit form" as a term used herein refers to physically discrete units suitable as unitary dosages for animal and human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired biological effect in association with the required pharmaceutical means.
Illustratively, a sterile injectable composition can be in the form of aqueous or oleagenous suspensions or solutions.
The sterile injectable composition can be aqueous or oleagenous suspension or solution. Suspensions can be formulated according to the known art using suitable dispersing and wetting agents and suspending agents. Solutions are similarly prepared from the salt form of the compound. For the laboratory animals, we prefer to use incomplete Freund's adjuvant or sterile saline (9%) as carrier. For human parenteral use, such as intramuscularly, intravenously, or by regional perfusion, the diluent can be a sterile aqueous vehicle containing a preservative; for example, methylparaben, propylparaben, phenyl, and chlorobutanol. The aqueous vehicle can also contain sodium chloride, preferably in an amount to be isotonic; as well as a suspending agent, for example, gum arabic, polyvinyl pyrrolidone, methyl cellulose, acetylated monoglyceride (available commercially as Myvacet from Distillation Products Industry, a division of Eastman Kodak Company), monomethyl glyceride, dimethyl glyceride, or a moderately high molecular weight polysorbitan (commercially available under the tradenames Tween or Span from Atlas Powder Company, Wilmington, Delaware). Other materials employed in the preparation of chemotherapeutic compositions containing the compound may include glutathione, 1,2-propanediol, glycerol, and glucose. Additionally, the pH of the composition is adjusted by use of an aqueous solution such as tris(hydroxymethyl)aminomethane (tris buffer).
Oily pharmaceutical carriers can also be used, since they dissolve the compound and permit high doses. Many oily carriers are commonly employed in pharmaceutical use, such as, for example, mineral oil, lard, cottonseed oil, peanut oil, sesame oil, or the like.
It is preferred to prepare the compositions, whether aqueous or oils, in a concentration in the range of from 2-50 mg./ml. Lower concentrations require needless quantities of liquid. Higher concentrations than 50 mg./ml. are difficult to maintain and are preferably avoided.
Oral administration forms of the drug can also be prepared for laboratory animals or human patients. The same dosage levels can be used as for injectable forms; however, even higher levels can be used to compensate for biodegradation in the transport. Generally, a solid unit dosage form can be prepared containing from 0.5 mg. to 25 mg. active ingredient.
Whatever the mode of administration, doses in the range of about 0.10 to 20 milligrams per kilogram of body weight administered one to four times per day are used, the exact dose depending on the age, weight, and condition of the patient and the frequency and route of administration.